The present invention relates generally to steroids, and in particular to a process for preparing 17xcex1-acetoxy-11xcex2-[4-N,N-(dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9-diene-3,20-dione, intermediates useful in the process, and processes for preparing such intermediates.
International patent application No. PCT/US 97/07373, filed Apr. 30, 1997, WO 97/41145, published Nov. 6, 1997, and U.S. provisional patent application No. 60/016,628, filed May 1, 1996, both assigned to the same assignee as the present application, disclose, inter alia, 17xcex1-acetoxy-11xcex2-[4-N,N-(dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9-diene-3,20-dione as an antiprogestational agent. This compound also is useful in other treatments, e.g., to induce menses or labor, to treat diseases such as endometriosis, dysmenorrhea, and endocrine hormone-dependent tumors, uterine fibroids, and to inhibit uterine endometrial proliferation.
The ""628 application discloses a method for preparing this compound, the method being outlined in FIG. 1 herein. As shown in FIG. 1, the cyanohydrin ketal (1) was converted to the silyl ether (2) by reaction with bromomethyldimethylsilyl chloride. Subsequent treatment with lithium diisopropylamide gave the 17xcex1-hydroxy-21-bromo derivative (3). Displacement of the 21-bromo substituent by acetate was effected by refluxing with potassium acetate in acetone to produce the 21-acetate (4). Hydrolysis of the crude 21-acetate (4) by potassium bicarbonate gave the 17xcex1,21-diol (5). Ketalization of the 17,21-diol-4,9-diene-3,20-dione (5) was achieved by reaction with ethylene glycol and tosic acid with water being removed by in vacuo azeotropic distillation. This produced the diketal (6). The less-hindered 21-hydroxyl group was selectively methylated with trimethyloxonium tetrafluoroborate using 1,8-bis(dimethylamino)-naphthalene as a base to provide the 21-methoxy compound (7).
Epoxidation of the 21-methoxy compound (7) with hexafluoroacetone trihydrate and 30% hydrogen peroxide produce a 2:1 mixture of 5xcex1,10xcex1- and 5xcex2,10xcex2-epoxides (8) as evidenced by NMR. As attempts to isolate pure 5xcex1,10xcex1-epoxide (8) were unsuccessful, the crude mixture was used directly on to the copper (I) catalyzed Grignard reaction, to obtain the 11xcex2-[4-(N,N-dimethylamino)phenyl] derivative (9). Hydrolysis with trifluoroacetic acid restored the 4,9-diene-3,20-dione structure (10). Acetylation of the 17xcex1-hydroxy compound (10) with the mixed anhydride formed from trifluoroacetic anhydride and acetic acid afforded the desired 19-norprogesterone compound (11).
While the method described in the ""628 application is satisfactory to produce the desired compound 11, there nevertheless remains a desire to provide a process for increasing the product yield. There further exists a desire for a process that employs reagents which need not be used in a large excess. There further exists a desire for a process that uses less expensive or safer reagents or conditions.
The advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
The present invention provides a process for preparing the compound of formula 11, that is, 17xcex1-acetoxy-11xcex2-[4-N,N-(dimethylamino)phenyl]-21-methoxy-19-norpregna-4,9-diene-3,20-dione, e.g., as shown in FIG. 2. The process of the present invention includes (a) replacing the cyanohydrin group of the compound of formula 1 with a 17-xcex2-chloroacetyl group-17-xcex1-hydroxyl group to obtain the compound of formula 12; (b) displacing the chloro group of the compound of formula 12 by an acetoxy group to obtain the compound of formula 4; (c) deacetylating the compound of formula 4 to obtain the compound of formula 5; (d) selectively ketalizing the compound of formula 5 to obtain the compound of formula 13; (e) selectively methylating the 21-hydroxyl group of the compound of formula 13 to obtain the compound of formula 14; (f) reducing the 20-ketone group of the compound of formula 14 to obtain the compound of formula 15; (g) epoxidizing the compound of formula 15 to obtain the 5xcex1,10xcex1-compound of formula 16; (h) introducing a N,N-dimethylaminophenyl group at the 11xcex2-position and concomitantly opening the epoxide ring of the compound of formula 16 to obtain the compound of formula 17; (i) deketalizing the compound of formula 17 to obtain the compound of formula 18; (j) selectively oxidizing the 20-hydroxyl group of the compound of formula 18 to a ketone group to obtain the compound of formula 10; and (k) acetylating the compound of formula 10 to obtain the compound of formula 11.
The process of the present invention has one or more advantages, e.g., it employs smaller quantities of or less expensive solvents and/or reagents. The process involves intermediates, reagents, or byproducts which are relatively safe to handle and to dispose of, and/or that are more efficiently used in the synthesis of the compound of formula 11. The process also provides the desired final compound as well as intermediates in relatively high quantities and purity levels. For example, an overall yield of from about 5 to about 6 percent or more can be achieved in preparing the compound of formula 11 starting from the compound of formula 1 using the process of the present invention. The process also involves purification methodologies that are easier to practice in a large scale compared to methods such as chromatography or distillation methodologies used heretofore. The process further involves less toxic reagents. One or more intermediates can be isolated upon evaporation of volatile solvents followed by aqueous precipitation. The process is less labor intensive and is scalable.
The present invention further provides novel intermediates useful in preparing the compound of formula 11. These intermediates include the compounds of formulae 12-18. The present invention further provides processes for preparing these intermediates. The present invention further provides a process for selectively oxidizing the secondary alcohol group of a composition containing secondary and tertiary alcohol groups. The selective oxidation process comprises treating the composition with a haloxybenzoic acid.
While the invention has been described and disclosed below in connection with certain preferred embodiments and procedures, it is not intended to limit the invention to those specific embodiments. Rather it is intended to cover all such alternative embodiments and modifications as fall within the spirit and scope of the appended claims.